The risk of serious reactions to local anesthetics might be minimized if one could reinforce the anesthetic potency of a local anesthetic drug without enhancing its toxicity. Our project investigates a new approach to this objective, based on two observation: (1) marked lowering of the extraaxonal sodium concentration reversibly augments the blocking action of local anesthetics on nerve conduction, (2) moderate hypoosmotic swelling of nerve appears to have an inhibitory effect on impulse conduction. The project will investigate the application of neural sodium depletion and neural osmotic swelling to the potentiation of currently used local anesthetics. In in vitro studies the neural sodium content and degree of osmotic swelling will be varied by incubating vagus nerve of rabbit in anesthetic solutions of varying sodium chloride concentration and varying hypoosmolarity. The intensity of local anesthetic conduction block will be measured by the amplitude of the compound action potential and compared under each set of conditions. In in vivo the neural pharmacokinetic characteristics and functional effects of selected solutions will be determined in standard animal models closely simulating clinical conditions. The effect on rapid axoplasmic transport, the local histological reaction of the tissues and the blood levels of anesthetic will be measured. Standard samples of exposed nerve and adjoining tissue will be subjected to semi-quantitative light and electron microscopic scrutiny for signs of tissue damage. The research will define the limits for a safe clinical trial.